Synthesis of 1-{4a,6-dimethyl-4a,9a-dihydropyrano-[3,4-b]indol-9(1H)-yl} ethanone

Article abstract of DOI:10.1134/S1070428012030086

Heating of the bromination product of 4-methyl-3,6-dihydro-2H-pyran with 4-toluidine or 2-bromo-4-methylamiline in triethylamine gave 4-methyl-N-(4-methylphenyl)- and N-(2-bromo-4-methylphenyl)- 4-methyl-3,6-dihydro-2H-pyran-3-amines which were converted into the corresponding amides by reaction with bromo- or chloroacetyl chloride. 1-{4a,6-Dimethyl-4a,9a-dihydropyrano[3,4-b]indol-9(1H)-yl}- ethanone was synthesized in good yield by heating N-(2-bromo-4-methylphenyl)-N-(4-methyl-3,6- dihydro-2Hpyran- 3-yl)acetamide in boiling toluene in the presence of palladium(II) acetate, triphenylphosphine, copper(II) acetate, triethylamine, and potassium carbonate. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012030086

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 383–386. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © D.A. Skladchikov, A.A. Fatykhov, R.R. Gataullin, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 3,
pp. 388–391.
Synthesis of 1-{4a,6-Dimethyl-4a,9a-dihydropyrano-
[3,4-b]indol-9(1H)-yl}ethanone
D. A. Skladchikov, A. A. Fatykhov, and R. R. Gataullin
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: gataullin@anrb.ru
Received June 13, 2011
Abstract—Heating of the bromination product of 4-methyl-3,6-dihydro-2H-pyran with 4-toluidine or
2-bromo-4-methylamiline in triethylamine gave 4-methyl-N-(4-methylphenyl)- and N-(2-bromo-4-methyl-
phenyl)-4-methyl-3,6-dihydro-2H-pyran-3-amines which were converted into the corresponding amides by
reaction with bromo- or chloroacetyl chloride. 1-{4a,6-Dimethyl-4a,9a-dihydropyrano[3,4-b]indol-9(1H)-yl}-
ethanone was synthesized in good yield by heating N-(2-bromo-4-methylphenyl)-N-(4-methyl-3,6-dihydro-2H-
pyran-3-yl)acetamide in boiling toluene in the presence of palladium(II) acetate, triphenylphosphine, copper(II)
acetate, triethylamine, and potassium carbonate.
DOI: 10.1134/S1070428012030086
Representatives of the pyranoindole series are few
in number; nevertheless, some pyranoindole deriva-
tives exhibit biological activity [1–3]. In the present
work we tried to build up fused pyranoindole system
by cyclization of a mixture of syn and anti atropiso-
mers of N-(2-bromo-4-methylphenyl)-N-(4-methyl-
3,6-dihydro-2H-pyran-3-yl)acetamide (IIa) under con-
ditions of metal complex catalysis, which is widely
used in the synthesis of nitrogen-containing hetero-
cycles [4, 5]. Compounds syn-IIa and anti-IIa were
synthesized by reaction of acetyl bromide with N-pyr-
anyl-substituted 2-bromo-4-methylaniline (I). The
latter was prepared by reaction of 2-bromo-4-methyl-
aniline [6] with the product of bromine addition to
4-methyl-3,6-dihydro-2H-pyran in carbon tetrachloride
[7] (Scheme 1).
5.64 ppm (anti). Likewise, by reaction of compound I
with chloroacetyl chloride we obtained a mixture of
1
13
syn and anti atropisomers IIb whose H and C NMR
spectra also contained double sets of some signals. For
comparison, amine III having no substituent in the
ortho position of the aromatic ring was converted into
1
compound IV, and its H NMR spectrum showed the
absence of atropisomerism.
Heterocyclization of amide IIa using the system
copper(II) acetate–palladium(II) acetate with addition
of triphenylphosphine, triethylamine, and potassium
carbonate gave dihydropyrano[3,4-b]indole (V) in
good yield. The reaction is likely to involve initial
formation of palladium intermediate A or B. Both
structures do not contradict published data [8–10].
Elimination of PdHL2Br from palladium derivative D
formed as a result of successive transformations yields
pyranoindole V.
The existence of compound IIa as two atropisomers
was determined by spectral methods. Signals in the
1H NMR spectra from the 3-H and 5-H protons in the
pyran ring were assigned to particular atropisomers on
the basis of published data [8]. According to the
1H NMR data, the syn/anti ratio was 1:3. The minor
syn atropisomer was characterized by a broadened
singlet from 3-H at δ 4.72 ppm. The corresponding
signal of the major anti isomer was observed in
a weaker field (δ 5.37 ppm, br.s). The 5-H proton
resonated as a broadened singlet at δ 5.47 (syn) or
The structure of compound V was determined on
the basis of its elemental composition and spectral
parameters. The mass spectrum of V contained the
molecular ion peak with m/z 244 [M + H]+. Signals in
1
the H NMR spectrum of V were assigned using HH
COSY, 1H–15N HMBC, and 1H–13C HSQC techniques.
cis-Junction of the pyran and pyrrole rings followed
from published data [8] for palladium-catalyzed
cyclization of cyclohexenylanilines and from nuclear
383

SKLADCHIKOV et al.
384
Scheme 1.
Me
O
Me
O
Br
Me
H
N
2-X-4-MeC6H3NH2
Et3N, Δ
Br
Br2, CCl4
Me
X
O
I, III
O
Cl
Me
AcBr or ClCH2COCl
K2CO3, CH2Cl2
N
Me
O
IV
3'
Br
Me
Br
N
O
Me
O
2'
1'
2
PdLn
Me
O
Pd(OAc)2, Cu(OAc)2, PPh3
Et3N, K2CO3, PhMe, Δ, 48 h
5
3
N
H
+
H
N
Y = H
Me
Br
Me
Me
2''
O
O
Me
Me
O
Y
Y
anti-IIa, anti-IIb
syn-IIa, syn-IIb
A
BrLnPd
Me
Br
Br
PdLn
PdLn
Me
Me
O
O
Me
N
N
N
H
O
Me
Me
O
O
Me
O
Me
B
C
D
Me
5
O
Me
4a
9a
9
N
–[PdHL2Br]
H
O
Me
V, 70%
I, IIa, IIb, X = Br; III, X = H; Y = H (a), Cl (b).
Overhauser effects between protons in the methyl
group on C4a, on the one hand, and 9a-H and 1-H, on
the other, in HH NOESY experiment. Such effect is
possible only for cis-junction of the above rings and
1,3-cis-diaxial orientation of the methyl group and
1-H. Here, the six-membered pyran ring should have
a conformation close to chair.
To conclude, we have developed a procedure for
the synthesis of 1-{4a,6-dimethyl-4a,9a-dihydropyrano-
[3,4-b]indol-9(1H)-yl}ethanone by bromination of
4-methyl-3,6-dihydro-2H-pyran, condensation of the
bromination product with 2-bromo-4-methylaniline,
acetylation, and palladium-catalyzed heterocyclization.
EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR
Presstige-21 spectrometer with Fourier transform. The
1H and 13C NMR spectra were measured on Bruker
AM 300 (300.13 and 75.45 MHz, respectively) and
Bruker Avance III 500 (500.13 and 125.73 MHz) in-
struments using tetramethylsilane as internal reference.
The elemental compositions were determined on
an M-185B CHN analyzer. The mass spectrum of com-
pound V (atmospheric pressure chemical ionization)
was obtained on an LCMS-2010EV instrument using
methanol–water (50:50) as eluent. The purity of liquid
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

SYNTHESIS OF 1-{4a,6-DIMETHYL-4a,9a-DIHYDROPYRANO[3,4-b]INDOL-9(1H)-YL}...
385
samples was determined on a Khromos GKh-1000 gas
chromatograph equipped with a flame ionization
detector and a 1000 × 3-mm column packed with
5% of SE-30 on Chromaton N-AW; carrier gas helium.
Qualitative TLC analysis was performed on Sorbfil
PTSKh-AF-V-UF plates (Sorbpolimer, Krasnodar);
spots were detected under UV light (λ 254 nm) or by
treatment with iodine vapor.
separated, washed with 10 ml of water, dried over
MgSO4, and evaporated, and the residue was purified
by chromatography on silica gel. Yield 0.97 g (55%),
Rf 0.25 (eight-shaped spot; C6H6–EtOAc, 9:1). IR
spectrum, ν, cm–1: 1737 m, 1697 m, 1660 s (C=O),
1610, 1514, 1490, 1371, 1311, 1240, 1139, 1107, 806.
1H NMR spectrum (CDCl3), δ, ppm: syn-IIa: 1.70 s,
1.90 s, 2.35 s (CH3); 3.60–3.73 m (3H, 6-H, 2-H),
4.35 d.d (1H, 6-H, J = 1.3, 12.2 Hz), 4.72 br.s (1H,
3-H), 5.47 br.s (1H, 5-H), 7.15 d (1H, 6′-H, J =
8.0 Hz), 7.40 s (1H, 3′-H), 7.55 d (1H, 5′-H, J =
8.0 Hz); anti-IIa: 1.75 s, 1.95 s, 2.40 s (CH3); 3.60–
3.73 m (1H, 2-H), 3.85 d.q (1H, 6-H, J = 1.6, 12.2 Hz),
4.10 m (1H, 2-H), 4.25 d.d (1H, 6-H, J = 1.6, 12.2 Hz),
5.37 br.s (1H, 3-H), 5.64 br.s (1H, 5-H), 6.90 d (1H,
6′-H, J = 8.0 Hz), 7.10 d (1H, 5′-H, J = 8.0 Hz), 7.50 s
(1H, 3′-H). 13C NMR spectrum (CDCl3), δC, ppm: syn-
IIa: 20.6, 22.2, 23.3 (CH3); 55.18 (C3), 65.0 and 67.9
(C2, C6), 124.5 (C4), 126.2 (C6′), 128.1 (C3′), 128.6
(C5), 129.4 (C4′), 133.5 (C5′), 137.2 (C2′), 139.3 (C1′),
171.2 (C=O); anti-IIa: 20.4, 20.7, 22.5 (CH3); 51.6
(C3), 64.8 and 66.7 (C2, C6), 124.8 (C4), 126.0 (C6′),
129.7 (C5), 130.5 (C4′), 131.5 (C3′), 134.0 (C5′), 136.9
(C2′), 139.6 (C1′), 171.0 (C=O). Found, %: C 55.49;
H 5.01; Br 24.58; N 4.26. C15H18BrNO2. Calculated,
%: C 55.57; H 5.60; Br 24.65; N 4.32.
N-(2-Bromo-4-methylphenyl)-4-methyl-3,6-dihy-
dro-2H-pyran-3-amine (I). A solution of 16 g (5.2 ml,
0.1 mol) of molecular bromine in 30 ml of carbon
tetrachloride was added dropwise under stirring to
a solution of 9.8 g (0.1 mol) of 4-methyl-3,6-dihydro-
2H-pyran in 30 ml of carbon tetrachloride on cooling
with ice. When the reaction was complete, the solvent
was removed under reduced pressure on a rotary evap-
orator, a solution of 18.6 g (0.1 mol) of 2-bromo-4-
methylaniline in 50 ml of triethylamine was added to
the residue, and the mixture was thoroughly stirred and
heated for 10 h under reflux. Triethylamine hydro-
bromide precipitated during the process. The mixture
was cooled to 20°C, a solution of 16 g of sodium
hydroxide in 100 ml of water was added, the mixture
was thoroughly shaken, and the organic phase was
separated, dried over KOH, and evaporated under
reduced pressure on a rotary evaporator, and the
residue was distilled under reduced pressure. Yield
16.9 g (60%), bp 150–156°C (2 mm). IR spectrum, ν,
cm–1: 3360 (NH), 1610, 1514, 1448, 1313, 1138, 1107,
4-Methyl-N-(4-methylphenyl)-3,6-dihydro-2H-
pyran-3-amine (III) was synthesized as described
above for compound I from 9.8 g of 4-methyl-3,6-
dihydro-2H-pyran and 10.7 g (0.1 mol) of 4-methyl-
aniline. Yield 13.6 g (67%), bp 125°C (2 mm). IR
spectrum, ν, cm–1: 3360 (NH), 1616, 1517, 808.
1
844, 804. H NMR spectrum (CDCl3), δ, ppm: 1.81 s
(3H, CH3), 2.22 s (3H, CH3), 3.68–3.73 m (2H, 2-H),
3.85 d.d (1H, 3-H, J = 2.0, 11.0 Hz), 4.06 d.quint (1H,
2
2
6-H, J = 2.0, J = 16.0 Hz), 4.20 d (1H, 6-H, J =
16.0 Hz), 4.34 br.s (1H, NH), 5.64 s (1H, 5-H), 6.80 d
(1H, 6′-H, J = 8.2 Hz), 6.97 d.d (1H, 5′-H, J = 1.8,
8.2 Hz), 7.28 d (1H, 3′-H, J = 1.8 Hz). Found, %:
C 55.21; H 5.65; Br 28.18; N 4.87. C13H16BrNO. Cal-
culated, %: C 55.33; H 5.72; Br 28.32; N 4.96.
2-Chloro-N-(4-methyl-3,6-dihydro-2H-pyran-3-
yl)-N-(4-methylphenyl)acetamide (IV). Compound
III, 3.03 g (15 mmol), was dissolved in 20 ml of meth-
ylene chloride, 2.8 g (20 mmol) of potassium carbon-
ate was added, and 1.70 g (15 mmol) of chloroacetyl
chloride was then added dropwise. The progress of the
reaction was monitored by TLC. When the initial
amine disappeared, the mixture was treated with 20 ml
of water under stirring, 150 ml of methylene chloride
was added, and the organic phase was separated,
washed with water (2×30 ml), and dried over MgSO4.
Removal of the solvent under reduced pressure left
3.3 g (78%) of a solid material, 31 mg of which was
recrystallized from benzene–petroleum ether (1:4).
N-(2-Bromo-4-methylphenyl)-N-(4-methyl-3,6-
dihydro-2H-pyran-3-yl)acetamide (IIa, a mixture of
syn and anti atropisomers). Compound I, 1.4 g
(5 mmol), was dissolved in 20 ml of methylene
chloride, and 2 ml of triethylamine and 0.44 ml
(6 mmol) of acetyl bromide were added under stirring.
The progress of the reaction was monitored by TLC; if
necessary, an additional amount (up to 1 equiv) of
acetyl bromide was added. When the reaction was
complete, the mixture was diluted with 60 ml of meth-
ylene chloride and treated with a saturated solution of
sodium hydrogen carbonate under vigorous stirring
(until CO2 no longer evolved). The organic phase was
1
Oblong crystals, mp 135–137°C. H NMR spectrum
(CDCl3), δ, ppm: 1.72 s (3H, CH3), 2.36 s (3H, CH3),
3.70–3.95 m (5H, 2-H, 6-Hax, CH2Cl), 4.12 d.d (1H,
2
6-Heq, J = 1.2, J = 12.0 Hz), 4.98 s (1H, 3-H), 5.52 s
(1H, 5-H), 7.10–7.30 m (4H, Harom). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

SKLADCHIKOV et al.
386
C 64.29; H 6.41; Cl 12.58; N 4.95. C15H18ClNO2.
Calculated, %: C 64.40; H 6.49; Cl 12.67; N 5.01.
residue was subjected to chromatography on silica gel
using benzene as eluent. Yield 0.238 g (70%), Rf 0.45
1
(benzene–ethyl acetate, 10:1). H NMR spectrum
N-(2-Bromo-4-methylphenyl)-2-chloro-N-
(4-methyl-3,6-dihydro-2H-pyran-3-yl)acetamide
(IIb, a mixture of syn and anti atropisomers) was
synthesized as described above for compound IV from
4.3 g (16.1 mmol) of amine I. The product was isolat-
ed by column chromatography on silica gel using
benzene–ethyl acetate (10:1) as eluent. First fractions
contained 1.72 g (40%) of unreacted amine I, and sub-
sequent elution gave 1.89 g (34%) of IIb as a mixture
(acetone-d6), δ, ppm: 1.30 s (3H, CH3), 2.27 s (3H,
CH3), 3.32 s (3H, CH3), 3.29 t (1H, 9a-H, J = 10.6 Hz),
4.20–4.35 m (2H, 1-H), 5.25 m (1H, 4-H), 6.50 d (1H,
3-H, J = 6.0 Hz), 7.00 d (1H, 8-H, J = 7.9 Hz), 7.10 s
(1H, 5-H), 7.90 d (1H, 8-H, J = 7.9 Hz). 13C NMR
spectrum (acetone-d6), δC, ppm: 21.0, 23.0, 29.3 (CH3);
42.1 (C4a), 64.6 (C9a), 64.7 (C1), 107.3 (C4), 118.3 (C8),
124.1 (C7), 128.5 (C5), 134.3 (C6), 138.3 (C8a), 141.6
(C4b), 144.2 (C3), 168.6 (C=O). 15N NMR spectrum
(acetone-d6): δN 140.8 ppm (N9). Mass spectrum, m/z:
244 [M + H]+, 202 [M + H – CH2CO]+, 158, 276 [M +
MeOH + H]+, 487 [2M + H]+. Found, %: C 73.98;
H 6.98; N 5.71. C15H17NO2. Calculated, %: C 74.05;
H 7.04; N 5.76.
1
of atropisomers, Rf 0.5 (C6H6–EtOAc, 9:1). H NMR
spectrum (CDCl3), δ, ppm: syn-IIb: 1.60 s (3H, CH3),
1.90 s (3H, CH3), 3.58–3.67 m (3H, 2-H, 6-H), 3.75 d
and 3.99 d (1H each, 2″-H, 2J = 13.3 Hz), 4.31 d.d (1H,
2
6-H, J = 1.6, J = 12.3 Hz), 4.07 s (1H, 3-H), 5.50 s
(1H, 5-H), 7.60 d (1H, 6′-H, J = 8.0 Hz), 7.14 d.d (1H,
5′-H, J = 1.8, 8.0 Hz), 7.44 d (1H, 3′-H, J = 1.8 Hz);
anti-IIb: 1.90 s (3H, CH3), 2.37 s (3H, CH3), 3.60–
The authors thank Academy of Sciences of Bash-
kortostan Republic for financial support of this work.
2
3.71 m (1H, 2-H), 3.75 d (1H, 2″-H, J = 13.3 Hz),
2
3.80 d.q (1H, 2-H, J = 2.5, J = 16.5 Hz), 3.94 d (1H,
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2
2″-H, J = 13.3 Hz), 4.05 m (1H, 6-H), 4.20 d.d (1H,
2
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N 3.91.
1-{4a,6-Dimethyl-4,9a-dihydropyrano[3,4-b]in-
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Pd(OAc)2, 52.4 mg (0.2 mmol) of PPh3, 0.28 ml
(0.3 mmol) of Et3N, 41.4 mg (0.3 mmol) of K2CO3,
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monitored by TLC. The mixture was then evaporated
under reduced pressure on a rotary evaporator, and the
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012